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Structure-Based Discovery of GPCR Ligands from Crystal Structures and Homology Models

  • Anirudh Ranganathan
  • David Rodríguez
  • Jens CarlssonEmail author
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 30)

Abstract

The G protein-coupled receptor (GPCR) superfamily constitutes the largest group of human membrane proteins and plays key roles in diverse cellular processes. Major advances in structural biology for GPCRs have provided invaluable insights into ligand recognition and signaling for these important drug targets. Access to high-resolution crystal structures also enables rational ligand design and in silico methods based on atomic-resolution models are likely to play an increasingly important role in future drug development. In this chapter, examples of ligand discovery efforts based on molecular docking screening against GPCR crystal structures will be presented first. Results from these studies suggest that crystal structures can not only guide discovery of ligands but also predict their selectivity and signaling properties. As experimental structures are not available for a large fraction of the superfamily, methods for atomic-resolution modeling of GPCR–ligand complexes could make important contributions to drug discovery. In the second part of the chapter, the state-of-the-art in this area is discussed in light of three community-wide assessments, which have challenged the modeling community to blindly predict GPCR structures. Finally, several recent examples of successful ligand discovery efforts utilizing atomic-resolution models for GPCRs of unknown structure are summarized.

Keywords

Agonist Antagonist Comparative modeling Drug discovery Fragment-based lead discovery G protein-coupled receptor Homology modeling Molecular docking Structure-based drug design Virtual screening 

Abbreviations

5-HT

5-Hydroxytryptamine, serotonin

ADR

Adrenergic receptor

AR

Adenosine receptor

CNS

Central nervous system

CXCR

C-X-C chemokine receptor

DR

Dopamine receptor

EL

Extracellular loop

FBLD

Fragment-based lead discovery

FLAP

Fingerprints for ligands and proteins

GPCR

G protein-coupled receptor

HR

Histamine receptor

HTS

High-throughput screening

IFP

Interaction fingerprint

IL

Intracellular loop

MC

Monte Carlo

MD

Molecular dynamics

mGluR

Metabotropic glutamate receptor

MR

Muscarinic receptor

MW

Molecular weight

NAM

Negative allosteric modulator

NECA

5′-N-ethylcarboxamidoadenosine

OR

Opioid receptor

PAINS

Pan-assay interference compounds

PAM

Positive allosteric modulator

PD

Parkinson’s disease

RMSD

Root-mean-square deviation

SMO

Smoothened receptor

TAAR1

Trace amine-associated receptor 1

TINS

Target immobilized NMR screening

TM

Transmembrane helix

Notes

Acknowledgements

This work was supported by grants from the Swedish Foundation for Strategic Research (ICA10-0098), Swedish Research Council (2013–05708), and the Science for Life Laboratory to J.C. The Sven och Lilly Lawski Foundation supported D.R. with a postdoctoral fellowship. A.R., D.R., and J.C. participate in the European COST Action CM1207 (GLISTEN).

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Anirudh Ranganathan
    • 2
  • David Rodríguez
    • 2
  • Jens Carlsson
    • 1
    Email author
  1. 1.Science for Life Laboratory, Department of Cell and Molecular Biology, Biomedical CenterUppsala UniversityUppsalaSweden
  2. 2.Science for Life Laboratory, Department of Biochemistry and BiophysicsStockholm UniversityStockholmSweden

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